The α7* nicotinic acetylcholine receptor encoded by CHRNA7 (human)/Chrna7 (mice) regulates the re... more The α7* nicotinic acetylcholine receptor encoded by CHRNA7 (human)/Chrna7 (mice) regulates the release of both the inhibitory neurotransmitter GABA and the excitatory neurotransmitter glutamate in the hippocampal formation. A heterozygous (Het) deletion at 15q13.3 containing CHRNA7 is associated with increased risk for schizophrenia, autism, and epilepsy. Each of these diseases are characterized by abnormalities in excitatory and inhibitory hippocampal circuit function. Reduced Chrna7 expression results in decreased hippocampal α7* receptor density, abnormal hippocampal auditory sensory processing, and increased hippocampal CA3 pyramidal neuron activity in C3H mice Het for a null mutation in Chrna7. These abnormalities demonstrate that decreased Chrna7 expression alters hippocampal inhibitory circuit function. The current study examined the specific impact of reduced Chrna7 expression on hippocampal inhibitory circuits by measuring the levels of GABA, GABA(A) receptors, the GABA syn...
Brain cholinergic dysfunction is associated with neuropsychiatric illnesses such as depression, a... more Brain cholinergic dysfunction is associated with neuropsychiatric illnesses such as depression, anxiety, and schizophrenia. Maternal stress exposure is associated with these same illnesses in adult offspring, yet the relationship between prenatal stress and brain cholinergic function is largely unexplored. Thus, using a rodent model, the current study implemented an intervention aimed at buffering the potential effects of prenatal stress on the developing brain cholinergic system. Specifically, control and stressed dams were fed choline-supplemented or control chow during pregnancy and lactation, and the anxiety-related behaviors of adult offspring were assessed in the open field, elevated zero maze and social interaction tests. In the open field test, choline supplementation significantly increased center investigation in both stressed and nonstressed female offspring, suggesting that choline-supplementation decreases female anxiety-related behavior irrespective of prenatal stress exposure. In the elevated zero maze, prenatal stress increased anxiety-related behaviors of female offspring fed a control diet (normal choline levels). However, prenatal stress failed to increase anxiety-related behaviors in female offspring receiving supplemental choline during gestation and lactation, suggesting that dietary choline supplementation ameliorated the effects of prenatal stress on anxiety-related behaviors. For male rats, neither prenatal stress nor diet impacted anxiety-related behaviors in the open field or elevated zero maze. In contrast, perinatal choline supplementation mitigated prenatal stress-induced social behavioral deficits in males, whereas neither prenatal stress nor choline supplementation influenced female social behaviors. Taken together, these data suggest that perinatal choline supplementation ameliorates the sex-specific effects of prenatal stress.
Prenatal stress (PS) impairs memory function; however, it is not clear whether PS-induced memory ... more Prenatal stress (PS) impairs memory function; however, it is not clear whether PS-induced memory deficits are specific to spatial memory, or whether memory is more generally compromised by PS. Here we sought to distinguish between these possibilities by assessing spatial, recognition and contextual memory functions in PS and nonstressed (NS) rodents. We also measured anxiety-related and social behaviors to determine whether our unpredictable PS paradigm generates a behavioral phenotype comparable to previous studies. Female Sprague-Dawley rats were exposed to daily random stress during the last gestational week and behavior tested in adulthood. In males but not females, PS decreased memory for novel objects and novel spatial locations, and facilitated memory for novel object/context pairings. In the elevated zero maze, PS increased anxiety-related behavior only in females. Social behaviors also varied with sex and PS condition. Females showed more anogenital sniffing regardless of stress condition. In contrast, prenatal stress eliminated a male-biased sex difference in nonspecific bodily sniffing by decreasing sniffing in males, and increasing sniffing in females. Finally, PS males but not females gained significantly more weight across adulthood than did NS controls. In summary, these data indicate that PS differentially impacts males and females resulting in sex-specific adult behavioral and bodily phenotypes.
Cognitive impairment is a common comorbidity in patients with Temporal Lobe Epilepsy (TLE). These... more Cognitive impairment is a common comorbidity in patients with Temporal Lobe Epilepsy (TLE). These impairments, particularly deficits in learning and memory, can be recapitulated in chemoconvulsant models of TLE. Here, we used two relatively low-stress behavioral paradigms, the novel object recognition task (NOR) and a spatial variation, the novel placement recognition task (NPR) to reveal deficits in short and long term memory, in both kainic acid (KA) and pilocarpine (Pilo) treated animals. We found that both KA- and Pilo-induced significant deficits in long term recognition memory but not short term recognition memory. Additionally, KA impaired spatial memory as detected by both NPR and Morris water maze. These deficits were present 1 week after SE. The characterization of memory performance of two chemoconvulsant-models, one of which is considered a surrogate organophosphate, provides an avenue for which targeted cognitive therapeutics can be tested.
Whereas the adolescent brain is a major target for gonadal hormones, our understanding of hormona... more Whereas the adolescent brain is a major target for gonadal hormones, our understanding of hormonal influences on adolescent neural and behavioral development remains limited. These experiments investigated how variations in the timing of testosterone (T) exposure, relative to adolescence, alters the strength of steroid-sensitive neural circuits underlying social behavior in male Syrian hamsters. Experiment 1 simulated early, on-time, and late pubertal development by gonadectomizing males on postnatal d 10 and treating with SILASTIC brand T implants for 19 d before, during, or after adolescence. T treatment before or during, but not after, adolescence facilitated mating behavior in adulthood. In addition, preadolescent T treatments most effectively increased mating behavior overall, indicating that the timing of exposure to pubertal hormones contributes to individual differences in adult behavior. Experiment 2 examined the effects of preadolescent T treatment on behavior and brain regional volumes within the mating neural circuit of juvenile males (i.e. still preadolescent). Although preadolescent T treatment did not induce reproductive behavior in juvenile males, it did increase volumes of the bed nucleus of the stria terminalis, sexually dimorphic nucleus, posterodorsal medial amygdala, and posteroventral medial amygdala to adult-typical size. In contrast, juvenile anterodorsal medial amygdala and ventromedial hypothalamus volumes were not changed by preadolescent T treatment yet differed significantly in volume from adult controls, suggesting that further maturation of these brain regions during adolescence is required for the expression of male reproductive behavior. Thus, adolescent maturation of social behavior may involve both steroid-independent and -dependent processes, and adolescence marks the end of a postnatal period of sensitivity to steroid-dependent organization of the brain.
Prenatal stress in humans is associated with psychiatric problems in offspring such as anxiety, d... more Prenatal stress in humans is associated with psychiatric problems in offspring such as anxiety, depression, and schizophrenia. These same illnesses are also associated with neuronal nicotinic acetylcholine receptor (nAChR) dysfunction. Despite the known associations between prenatal stress exposure and offspring mental illness, and between mental illness and nAChR dysfunction, it is not known whether prenatal stress exposure impacts neuronal nAChRs. Thus, we tested the hypothesis that maternal stress alters the development of hippocampal alpha4 beta2 (α4β2∗) and alpha7 (α7∗) nicotinic receptor levels in adult offspring. Female Sprague-Dawley rats experienced unpredictable variable stressors two to three times daily during the last week of gestation. At weaning (21 days) the offspring of prenatally stressed (PS) and nonstressed (NS) dams were assigned to same-sex PS or NS groups. In young adulthood (56 days), the brains of offspring were collected and adjacent sections processed for quantitative autoradiography using [125I]-epibatidine (α4β2* nicotinic receptor-selective) and [125I]-α-bungarotoxin (α-BTX; α7* nicotinic receptor-selective) ligands. We found that PS significantly increased hippocampal α4β2* nAChRs of males and females in all subfields analyzed. In contrast, only females showed a trend toward PS-induced increases in α7* nAChRs in the dentate gyrus. Interestingly, NS females displayed a significant left-biased lateralization of α7* nAChRs in the laconosum moleculare of area CA1, whereas PS females did not, suggesting that PS interfered with normal lateralization patterns of α7* nAChRs during development. Taken together, our results suggest that PS impacts the development of hippocampal nAChRs, which may be an important link between PS exposure and risk for neuropsychiatric illness.
The medial amygdala (Me), a brain region essential for mating behavior, changes in size during pu... more The medial amygdala (Me), a brain region essential for mating behavior, changes in size during puberty. In pre-, mid-, and late pubertal (21, 35, and 49 days of age) male Syrian hamsters, we examined neuronal structure in Me and protein levels of spinophilin and synaptophysin in the amygdaloid complex for evidence of synaptic plasticity coincident with behavioral and physiological development. Body weight, testes weight, and testosterone levels increased during puberty. Mounting behavior, including ectopic, nonintromittive, and intromittive mounts, also increased. Neuronal structure in the posterodorsal medial amygdala (MePD) was assessed in Golgi-impregnated neurons. Pruning occurred during puberty in the number of dendrites emanating from the cell body and in terminal dendritic spine densities. Approximately half of all MePD neurons analyzed had an axon emanating from a dendrite rather than the cell body. However, prepubertal males were more likely to have the axon emanating from a higher order dendritic segment (secondary or tertiary) than were mid- and late pubertal males. Finally, protein levels in the amygdaloid complex varied with pubertal age. Spinophilin decreased, while synaptophysin and GAPDH protein levels increased. These results suggest that puberty is a period of dramatic synaptic plasticity in Me. Specifically, pruning of dendrites and spines, in combination with axonal changes, is likely to modify the afferent influences and electrophysiological properties of Me neurons. Because the Me is an integral component of a social behavior neural network, these changes may be related not only to sexual behavior, but also to other behaviors that mature during puberty, including aggressive, risk-taking, fear-related, and parental behaviors.
The α7* nicotinic acetylcholine receptor encoded by CHRNA7 (human)/Chrna7 (mice) regulates the re... more The α7* nicotinic acetylcholine receptor encoded by CHRNA7 (human)/Chrna7 (mice) regulates the release of both the inhibitory neurotransmitter GABA and the excitatory neurotransmitter glutamate in the hippocampal formation. A heterozygous (Het) deletion at 15q13.3 containing CHRNA7 is associated with increased risk for schizophrenia, autism, and epilepsy. Each of these diseases are characterized by abnormalities in excitatory and inhibitory hippocampal circuit function. Reduced Chrna7 expression results in decreased hippocampal α7* receptor density, abnormal hippocampal auditory sensory processing, and increased hippocampal CA3 pyramidal neuron activity in C3H mice Het for a null mutation in Chrna7. These abnormalities demonstrate that decreased Chrna7 expression alters hippocampal inhibitory circuit function. The current study examined the specific impact of reduced Chrna7 expression on hippocampal inhibitory circuits by measuring the levels of GABA, GABA(A) receptors, the GABA syn...
Brain cholinergic dysfunction is associated with neuropsychiatric illnesses such as depression, a... more Brain cholinergic dysfunction is associated with neuropsychiatric illnesses such as depression, anxiety, and schizophrenia. Maternal stress exposure is associated with these same illnesses in adult offspring, yet the relationship between prenatal stress and brain cholinergic function is largely unexplored. Thus, using a rodent model, the current study implemented an intervention aimed at buffering the potential effects of prenatal stress on the developing brain cholinergic system. Specifically, control and stressed dams were fed choline-supplemented or control chow during pregnancy and lactation, and the anxiety-related behaviors of adult offspring were assessed in the open field, elevated zero maze and social interaction tests. In the open field test, choline supplementation significantly increased center investigation in both stressed and nonstressed female offspring, suggesting that choline-supplementation decreases female anxiety-related behavior irrespective of prenatal stress exposure. In the elevated zero maze, prenatal stress increased anxiety-related behaviors of female offspring fed a control diet (normal choline levels). However, prenatal stress failed to increase anxiety-related behaviors in female offspring receiving supplemental choline during gestation and lactation, suggesting that dietary choline supplementation ameliorated the effects of prenatal stress on anxiety-related behaviors. For male rats, neither prenatal stress nor diet impacted anxiety-related behaviors in the open field or elevated zero maze. In contrast, perinatal choline supplementation mitigated prenatal stress-induced social behavioral deficits in males, whereas neither prenatal stress nor choline supplementation influenced female social behaviors. Taken together, these data suggest that perinatal choline supplementation ameliorates the sex-specific effects of prenatal stress.
Prenatal stress (PS) impairs memory function; however, it is not clear whether PS-induced memory ... more Prenatal stress (PS) impairs memory function; however, it is not clear whether PS-induced memory deficits are specific to spatial memory, or whether memory is more generally compromised by PS. Here we sought to distinguish between these possibilities by assessing spatial, recognition and contextual memory functions in PS and nonstressed (NS) rodents. We also measured anxiety-related and social behaviors to determine whether our unpredictable PS paradigm generates a behavioral phenotype comparable to previous studies. Female Sprague-Dawley rats were exposed to daily random stress during the last gestational week and behavior tested in adulthood. In males but not females, PS decreased memory for novel objects and novel spatial locations, and facilitated memory for novel object/context pairings. In the elevated zero maze, PS increased anxiety-related behavior only in females. Social behaviors also varied with sex and PS condition. Females showed more anogenital sniffing regardless of stress condition. In contrast, prenatal stress eliminated a male-biased sex difference in nonspecific bodily sniffing by decreasing sniffing in males, and increasing sniffing in females. Finally, PS males but not females gained significantly more weight across adulthood than did NS controls. In summary, these data indicate that PS differentially impacts males and females resulting in sex-specific adult behavioral and bodily phenotypes.
Cognitive impairment is a common comorbidity in patients with Temporal Lobe Epilepsy (TLE). These... more Cognitive impairment is a common comorbidity in patients with Temporal Lobe Epilepsy (TLE). These impairments, particularly deficits in learning and memory, can be recapitulated in chemoconvulsant models of TLE. Here, we used two relatively low-stress behavioral paradigms, the novel object recognition task (NOR) and a spatial variation, the novel placement recognition task (NPR) to reveal deficits in short and long term memory, in both kainic acid (KA) and pilocarpine (Pilo) treated animals. We found that both KA- and Pilo-induced significant deficits in long term recognition memory but not short term recognition memory. Additionally, KA impaired spatial memory as detected by both NPR and Morris water maze. These deficits were present 1 week after SE. The characterization of memory performance of two chemoconvulsant-models, one of which is considered a surrogate organophosphate, provides an avenue for which targeted cognitive therapeutics can be tested.
Whereas the adolescent brain is a major target for gonadal hormones, our understanding of hormona... more Whereas the adolescent brain is a major target for gonadal hormones, our understanding of hormonal influences on adolescent neural and behavioral development remains limited. These experiments investigated how variations in the timing of testosterone (T) exposure, relative to adolescence, alters the strength of steroid-sensitive neural circuits underlying social behavior in male Syrian hamsters. Experiment 1 simulated early, on-time, and late pubertal development by gonadectomizing males on postnatal d 10 and treating with SILASTIC brand T implants for 19 d before, during, or after adolescence. T treatment before or during, but not after, adolescence facilitated mating behavior in adulthood. In addition, preadolescent T treatments most effectively increased mating behavior overall, indicating that the timing of exposure to pubertal hormones contributes to individual differences in adult behavior. Experiment 2 examined the effects of preadolescent T treatment on behavior and brain regional volumes within the mating neural circuit of juvenile males (i.e. still preadolescent). Although preadolescent T treatment did not induce reproductive behavior in juvenile males, it did increase volumes of the bed nucleus of the stria terminalis, sexually dimorphic nucleus, posterodorsal medial amygdala, and posteroventral medial amygdala to adult-typical size. In contrast, juvenile anterodorsal medial amygdala and ventromedial hypothalamus volumes were not changed by preadolescent T treatment yet differed significantly in volume from adult controls, suggesting that further maturation of these brain regions during adolescence is required for the expression of male reproductive behavior. Thus, adolescent maturation of social behavior may involve both steroid-independent and -dependent processes, and adolescence marks the end of a postnatal period of sensitivity to steroid-dependent organization of the brain.
Prenatal stress in humans is associated with psychiatric problems in offspring such as anxiety, d... more Prenatal stress in humans is associated with psychiatric problems in offspring such as anxiety, depression, and schizophrenia. These same illnesses are also associated with neuronal nicotinic acetylcholine receptor (nAChR) dysfunction. Despite the known associations between prenatal stress exposure and offspring mental illness, and between mental illness and nAChR dysfunction, it is not known whether prenatal stress exposure impacts neuronal nAChRs. Thus, we tested the hypothesis that maternal stress alters the development of hippocampal alpha4 beta2 (α4β2∗) and alpha7 (α7∗) nicotinic receptor levels in adult offspring. Female Sprague-Dawley rats experienced unpredictable variable stressors two to three times daily during the last week of gestation. At weaning (21 days) the offspring of prenatally stressed (PS) and nonstressed (NS) dams were assigned to same-sex PS or NS groups. In young adulthood (56 days), the brains of offspring were collected and adjacent sections processed for quantitative autoradiography using [125I]-epibatidine (α4β2* nicotinic receptor-selective) and [125I]-α-bungarotoxin (α-BTX; α7* nicotinic receptor-selective) ligands. We found that PS significantly increased hippocampal α4β2* nAChRs of males and females in all subfields analyzed. In contrast, only females showed a trend toward PS-induced increases in α7* nAChRs in the dentate gyrus. Interestingly, NS females displayed a significant left-biased lateralization of α7* nAChRs in the laconosum moleculare of area CA1, whereas PS females did not, suggesting that PS interfered with normal lateralization patterns of α7* nAChRs during development. Taken together, our results suggest that PS impacts the development of hippocampal nAChRs, which may be an important link between PS exposure and risk for neuropsychiatric illness.
The medial amygdala (Me), a brain region essential for mating behavior, changes in size during pu... more The medial amygdala (Me), a brain region essential for mating behavior, changes in size during puberty. In pre-, mid-, and late pubertal (21, 35, and 49 days of age) male Syrian hamsters, we examined neuronal structure in Me and protein levels of spinophilin and synaptophysin in the amygdaloid complex for evidence of synaptic plasticity coincident with behavioral and physiological development. Body weight, testes weight, and testosterone levels increased during puberty. Mounting behavior, including ectopic, nonintromittive, and intromittive mounts, also increased. Neuronal structure in the posterodorsal medial amygdala (MePD) was assessed in Golgi-impregnated neurons. Pruning occurred during puberty in the number of dendrites emanating from the cell body and in terminal dendritic spine densities. Approximately half of all MePD neurons analyzed had an axon emanating from a dendrite rather than the cell body. However, prepubertal males were more likely to have the axon emanating from a higher order dendritic segment (secondary or tertiary) than were mid- and late pubertal males. Finally, protein levels in the amygdaloid complex varied with pubertal age. Spinophilin decreased, while synaptophysin and GAPDH protein levels increased. These results suggest that puberty is a period of dramatic synaptic plasticity in Me. Specifically, pruning of dendrites and spines, in combination with axonal changes, is likely to modify the afferent influences and electrophysiological properties of Me neurons. Because the Me is an integral component of a social behavior neural network, these changes may be related not only to sexual behavior, but also to other behaviors that mature during puberty, including aggressive, risk-taking, fear-related, and parental behaviors.
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